The formation of fibrovascular adhesions is a complication of surgery. The problems caused by these adhesions are varied and depend on the anatomical location of the surgical procedure. Peritoneal adhesions in abdominal surgery and peridural adhesions after laminectomy are two examples of this problem. In cardiac surgery, postoperative adhesions forming between the heart, pericardium and sternum, may place the mediasternal structures hazardously close to the path of dissection required in a subsequent procedure. Over 360,000 cardiac procedures are performed annually in the United States, of which 43,000 are re-operations (J. Thor Cardiovasc. Surg., vol. 94, pp. 291-6 (1987)). Approximately 4% of patients undergoing re-operation experience complications, for example, hemorrhage, related to repeated sternal opening. If hemorrhage does occur, there is a mortality risk of approximately 37% (Ann. Thorac. Surg., vol. 37, pp. 273-8.(1984)). Adhesion formation after cardiac surgery thus increases the costs and risks of a second cardiac procedure.
A number of methods have been evaluated to prevent adhesions after surgery. For example, in cardiac surgery, the placement of aldehyde-fixed xenografts, such as bovine pericardium, may calcify and fibrose, exacerbating the problem (Thorac. Cardiovasc. Surg., vol. 30, pp. 306-9 (1982)). Animal studies have shown that the use of synthetic membranes is accompanied by a risk of closing the pericardium completely, and a risk of an accumulated pericardial effusion and tamponade (J. Surg. Res., vol. 78, pp. 118-22 (1998)). Less rigid membranes are under development, but are less likely to reduce posterior/dorsal epicardial adhesions and would be difficult to use in thoracoscopic procedures. Overall, the medical need for an adhesion prevention material that can be placed over the heart via a thoracoscopic procedure has not been met.
In one type of articular surgery, in order to prevent accretions of cartilaginous tissue, rigid, non-bioabsorbable silicon plates are surgically introduced. The techniques presently available necessitate surgical removal of the plates, after a suitable period of time. There is a need for an adhesion prevention material which is rigid enough to be used in this type of articular surgery, but which does not have to be surgically removed.
Although it has exceptional biocompatibility, and has been used in a number of biomedical applications, native, uncross-linked hyaluronic acid (xe2x80x9cHAxe2x80x9d) is generally not effective in reducing postoperative adhesions. Modified, water-insoluble derivatives of HA have been used as an aid to prevent adhesions or accretions of body tissues during the post-operation period. The method of forming the derivative, and its use in gels, films and sponges as surgical aids to prevent adhesions of body tissues and as drug delivery vehicles are described in U.S. Pat. No. 5,356,883, to Kuo et al., issued on Oct. 18, 1994. Generally, the method includes forming a water-insoluble gel by reacting HA, or a salt thereof, with a carbodiimide in the absence of a nucleophile or a polyanionic polysaccharide. The teachings of U.S. Pat. No. 5,356,883 are incorporated herein by reference in their entirety.
The present invention is directed to a composite and a method for reducing post-operative adhesion of tissues.
The composite includes a biocompatible, biodegradable support and hyaluronic acid derivative at the support. The hyaluronic acid derivative includes an N-acylurea that is formed by reaction of hyaluronic acid with a multifunctional carbodiimide. In another embodiment, at least 25 percent of derivatized functionalities of the hyaluronic acid derivative are O-acylisoureas or N-acylureas.
In still another embodiment, the invention is a drug delivery vehicle. The drug delivery vehicle includes a biocompatible-biodegradable support and a hyaluronic acid derivative component at the biocompatible-biodegradable support. The hyaluronic acid derivative component includes an N-acylurea that is formed by reaction of hyaluronic acid with a multifunctional carbodiimide. The drug delivery vehicle also includes a pharmaceutically active molecule at the hyaluronic acid derivative component.
In a further embodiment, the hyaluronic acid derivative component of the composite or the drug delivery vehicle is formed by reaction of hyaluronic acid with a multifunctional carbodiimide and a monocarbodiimide.
Another embodiment of the invention is a method of forming a composite for reducing post-operative adhesion of tissues. The method includes applying a hyaluronic acid derivative to a biocompatible-biodegradable support. The hyaluronic acid derivative includes an N-acylurea that results from reaction of hyaluronic acid with a multifunctional carbodiimide. In one embodiment, at least 25 percent of derivatized functionalities of the hyaluronic acid derivative are O-acylisoureas or N-acylureas.
In another embodiment, a method of preparing a drug delivery vehicle includes applying a hyaluronic acid derivative component to a biocompatible-biodegradable support. The hyaluronic acid derivative includes N-acylurea that results from reaction of hyaluronic acid with a multifunctional carbodiimide. The hyaluronic acid derivative component also includes a pharmaceutically-active molecule.
In another embodiment, a method of the invention includes forming a composite for reducing post-operative adhesion of tissue by applying a hyaluronic acid derivative component to a biocompatible-biodegradable support, wherein the hyaluronic acid derivative component includes an N-acylurea that is the reaction product of hyaluronic acid, a multifunctional carbodiimide, and a monocarbodiimide.
In still another embodiment, the method includes introducing to tissues at a surgical site a composite that includes a biocompatible-biodegradable support, and a derivatized hyaluronic acid component at the support. The derivatized hyaluronic acid component is the reaction product of hyaluronic acid and a multifunctional carbodiimide.
This invention has many advantages. For example, it provides a post-operative adhesion barrier that is at least substantially resorbable, and therefore generally does not need to be surgically removed at a later date. It also is relatively easy to use, is capable of being sutured, and tends to stay in place after it is applied. A further advantage is that it can supply modified HA in a sustained release manner over a prolonged period of time. The invention also provides a drug delivery system which can be easily injected or implanted at a particular site, where it provides sustained release of the drug.